I. Segmentation
Segmentation is a basic characteristic of many animal species ranging from invertebrates, such as insects, to vertebrates, such as humans. Body segmentation usually corresponds to repetition of similar structures consisting of derivatives from the three embryonic germ layers. In humans, segmentation is most obvious at the level of the vertebral column and its associated musculature, as well as in the peripheral nervous system. The segmented distribution of the vertebrae derives from the earlier metameric pattern of the embryonic somites.
Segmentation is visualized morphologically by the sequential formation of bilateral blocks of cells, the somites, from the rostral extremity of the presomitic mesoderm (PSM). In most vertebrates, somites are further subdivided into an anterior and posterior compartment. This subdivision is important for later patterning events, such as the formation of the vertebrae which are formed through the fusion of the posterior part of a somite to the anterior part of the consecutive somite in a process called resegmentation. This partitioning of the somite is also critical for establishing the peripheral nervous system (PNS) segmentation since motor neuron axons and neural crest cells are only allowed to migrate in the anterior part of the somite, thus resulting in the segmented aspect of the PNS. Formation of the somites occurs in the rostral PSM and relies on a molecular oscillator called the segmentation clock which requires both Notch and Wnt signaling. (Pourquie, Annual Review Cell Dev Biol, 17-311-350 (2001).)
II. Genetically Defective Segmentation
In humans, defects in the early stages of the vertebral column formation can result in a wide range of vertebral and rib malformations often grouped as congenital scoliosis or spondylocostal dysostoses (SCD). These malformations are very severe but the frequency of such malformations is quite low (1 or 2 per 10,000 births). The vertebral anomalies result in worsening spinal deformity with growth. Surgical spine fusion may be necessary to correct and stop the spinal curvature. These disorders are characterized radiologically by multiple vertebral segmentation defects and rib anomalies, which are frequently misaligned with their points of fusion and sometimes reduced in number. (Turnpenny et al, J. Med. Genet 40:333-339 (2003).)
Sporadic cases of SCD occur more commonly than familial ones and are more likely to be associated with multiple congenital abnormalities. In contrast, monogenic forms more commonly demonstrate autosomal recessive (AR) rather than autosomal dominant (AD) inheritance. Associated features in familial cases include anal and urogenital anomalies, congenital heart disease, limb abnormalities, plagiocephaly-torticollis sequences, and inguinal herniae in males.
Thus far, only three genes, Delta-like3 (DLL3), Lunatic fringe (Lfng) and Mesoderm postertior 2 (Mesp2), each of which is linked to the segmentation clock oscillator, have been associated with such heritable syndromes in humans. Twenty four distinct mutations have been found in DLL3 (SCD1 [MIM 277300]) and associated with SCD. (Bulman et al. 2000; Sparrow et al. 2002; Bonafé et al. 2003; Turnpenny et al. 2003; Whittock et al, 2004a). A single, missense mutation was identified in Lfng in a highly conserved phenylalanine close to the active site of the enzyme that caused it to become inactive. Sparrow, et at (2006). A single mutation to Mesp2 (SCD)2 [MIM 608681]) has also been identified (Whittock et al. 2004b).
In the mouse, additional and different mutations to the Notch signaling pathway, which is central to somite formation, have been identified (e.g. Notch1, DLL3, DLL1, Lfng, Psen1, and Csl), and mutation to a downstream target gene (hes7) also results in abnormal somitogenesis. Reviewed by Weinmaster and Kintner (2003).
The aforementioned studies recognized that the molecular defects underlying most of the congenital scoliosis cases remain unknown. In fact, most cases of congenital scoliosis are not identified in humans until a fetus is well-developed, or a child is born. Presently, because the underlying cause of most of these disorders is unknown, the ability to proactively identify families and couples at risk for having children with any of these disorders is severely limited or impossible.